The muscular dystrophies (MD) are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Some forms of MD are seen in infancy or childhood, while others may not appear until middle age or later. The disorders differ in terms of the distribution and extent of muscle weakness (some forms of MD also affect cardiac muscle), age of onset, rate of progression, and pattern of inheritance. Duchenne MD is the most common form of MD and primarily affects boys. It is caused by the absence of dystrophin, a protein involved in maintaining the integrity of muscle. Onset is between 3 and 5 years and the disorder progresses rapidly. Most boys are unable to walk by age 12, and later need a respirator to breathe. Girls in these families have a 50 percent chance of inheriting and passing the defective gene to their children. Boys with Becker MD (very similar to but less severe than Duchenne MD) have faulty or not enough dystrophin. Facioscapulohumeral MD usually begins in the teenage years. It causes progressive weakness in muscles of the face, arms, legs, and around the shoulders and chest. It progresses slowly and can vary in symptoms from mild to disabling. Myotonic MD is the disorder's most common adult form and is typified by prolonged muscle spasms, cataracts, cardiac abnormalities, and endocrine disturbances. Individuals with myotonic MD have long, thin faces, drooping eyelids, and a swan-like neck. Muscular dystrophies are caused by progressive degeneration of skeletal muscle fibres. Lack of one of several proteins located either at the plasma membrane [1] or, less frequently, within internal membranes [2] increases the probability of damage during contraction, and eventually leads to fibre degeneration, accompanied by severe local inflammation with infiltration of immune-competent cells [3,4]. In the most severe forms, such as Duchenne Muscular Dystrophy, regeneration is exhausted and skeletal muscle is progressively replaced by fat and fibrous tissue. This condition leads the patient to progressive weakness and eventually death by respiratory and/or cardiac failure.
The current therapeutic approaches to muscular dystrophies involve steroids, such as prednisolone and deflazacort, and dantrolene, administered in various protocols. These treatments result in modest beneficial effects and are accompanied by severe side-effects including osteoporosis, hypertension, Cushing syndrome, weight gain, cataracts, short stature, gastrointestinal symptoms, behavioural changes in the case of steroids, and liver damage with dantrolene [5-7]. With steroids, moreover there is no consensus regarding their use as standard treatment. Alternative therapeutic approaches to muscular dystrophies have been proposed, and various compounds and drugs tested. None of them has yielded favourable outcomes in clinical trials and entered the clinical practice [5].
Thus there is a need to identify therapeutic agents which slow the muscle fibre damage and delay the onset of disability in patients with muscular dystrophies more efficiently than the current therapies and causing a lesser degree of side effects. The beneficial effect of corticosteroids is believed to reside in the blocking of immune cell activation and infiltration which are precipitated by muscle fibre damage resulting from the disease [3,4]. Nitric oxide (NO) generated by a muscular NO synthase structurally and functionally linked to the dystrophin complex at the sarcolemma participates to physiological development and function of skeletal muscle. In particular it regulates excitation-contraction coupling, in such a way that it prevents the muscle from being damaged during its contractile activity. In addition, NO couples muscle function to energy availability by promoting vasodilation and thus supply of oxygen during exercise, by increasing glucose uptake in the myofibres, and by regulating the activity of enzymes relevant to cell energy metabolism [8-9].
NSAIDs are known to reduce inflammation through inhibition of cyclooxygenases 1 and 2 [10]. The authors found that the combination of nitric oxide-releasing compounds and NSAIDs is effective in retarding the development of, or reversing muscular dystrophies. Moreover these compounds, for which a novel use is proposed, are known to cause less side effects than current therapies for muscular dystrophy. They are in general well tolerated by the patients and are suitable for long-term therapies.